Oral dosing formulations of dideoxy purine nucleosides

Abstract

Improved oral dosage formulations for acid-labile dideoxy purine nucleoside derivatives such as ddA, ddI, and ddG, have been developed by incorporating selected water-insoluble buffering systems in the formulation. These novel formulations provide reduced mass dosage units in the form of convenient, palatable chewable/dispersible tablets or a dry powder sachet. The reduced mass requirement, necessary to allow tablets of reasonable size, was achieved in part by an unexpected 20 to 25% increase in drug bioavailability resulting from use of the selected buffering systems comprised of an insoluble magnesium antacid agent and either dihydroxyaluminum sodium carbonate or calcium carbonate.

We claim: 
     
       1. A pharmaceutical composition for oral delivery of dideoxypurine nucleosides with improved bioavailability, the composition comprising; from about 5 to 375 mg per dosing unit of a dideoxy purine nucleoside selected from the group consisting of 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxyguanosine (ddG), and individual pharmaceutically acceptable salts, prodrug esters, and hydrates thereof;   and about 800 to 2800 mg of a water-insoluble antacid buffering composition which contains a water insoluble antacid magnesium compound selected from the group consisting of magnesium carbonate, magnesium carbonate hydroxide, magnesium hydroxide, magnesium oxide, magnesium (tribasic) phosphate and magnesium trisilicate,   combined with a dihydroxyaluminum alkali metal carbonate or with calcium carbonate;   optionally containing a soluble citrate buffer;   and which optionally additionally contains binders, disintegrants, sweeteners, flavoring agents, and other pharmaceutically acceptable excipients;   with the proviso that the formulation does not act like a bulk laxative, cause constipation, or cause either physiological pH or electrolyte imbalances in the host following administration.   
     
     
       2. The pharmaceutical composition of claim 1 wherein the water-insoluble antacid buffering composition contains one part of a water-insoluble antacid magnesium compound in combination with about 2 to 4 parts of a dihydroxyaluminum alkali metal carbonate or with about 1.5 to 3 parts of calcium carbonate.   
     
     
       3. A chewable oral tablet formulation that may chewed or dispersed in a liquid and swallowed, the tablet formulation containing the pharmaceutical composition of claim 1. 
     
     
       4. The composition of claim 1 containing a sweetening agent. 
     
     
       5. The composition of claim 4 wherein the sweetening agent is selected from the group consisting of aspartame, sorbitol and sucrose. 
     
     
       6. The composition of claim 1 containing a flavoring agent. 
     
     
       7. The composition of claim 1 containing a disintegrant. 
     
     
       8. The composition of claim 1 containing a binder. 
     
     
       9. The composition of claim 1 containing pharmaceutically acceptable excipients. 
     
     
       10. The composition of claim 1 wherein the dideoxy purine nucleoside is ddI. 
     
     
       11. The composition of claim 1 wherein the water-insoluble antacid buffering composition contains a dihydroxyaluminum alkali metal carbonate. 
     
     
       12. The composition of claim 11 wherein the water-insoluble antacid buffering composition contains dihydroxyaluminum sodium carbonate. 
     
     
       13. The composition of claim 1 wherein the water-insoluble antacid buffering composition contains calcium carbonate. 
     
     
       14. The composition of claim 1 wherein the water-insoluble antacid magnesium compound is magnesium hydroxide. 
     
     
       15. The composition of claim 1 containing -ddI, dihydroxyaluminum sodium carbonate, magnesium hydroxide, a soluble citrate antacid buffer, a sweetening agent, and a flavoring agent. 
     
     
       16. The composition of claim 1 containing -ddI, calcium carbonate, magnesium hydroxide, a sweetening agent, and a flavoring agent. 
     
     
       17. An oral tablet formulation containing the pharmaceutical composition of claim 15. 
     
     
       18. An oral tablet formulation containing the pharmaceutical composition of claim 16. 
     
     
       19. An oral powder formulation for dispersal in a liquid and containing the pharmaceutical composition of claim 1. 
     
     
       20. An oral powder formulation for dispersal in a liquid and containing the pharmaceutical composition of claim 15. 
     
     
       21. An oral powder formulation for dispersal in a liquid and containing the pharmaceutical composition of claim 16. 
     
     
       22. A chewable or dispersible tablet formulation comprising from about 5 to 375 mg of ddI; about 1.3 to 1.4 g of dihydroxyaluminum sodium carbonate; about 0.4 to 0.5 g of magnesium hydroxide; about 0.3 g of sodium citrate dihydrate; about 0.06 g aspartame and about 0.16 g sucrose; about 0.075 g tablet disintegrant, about 0.04 g silicon dioxide; about 0.02 g wintergreen flavor; about 0.05 g magnesium stearate; and sufficient microcrystalline cellulose to yield a tablet weighing about 3.0 g. 
     
     
       23. A chewable or dispersible tablet formulation comprising about 5 to 375 mg of ddI; about 0.5 to 0.6 g calcium carbonate; about 0.2 to 0.3 g magnesium hydroxide; about 0.06 g aspartame; about 0.08 g tablet disintegrant; about 0.02 g silicon dioxide; about 0.05 g orange flavor; about 0.02 g magnesium stearate and sufficient microcrystalline cellulose to yield a tablet weighing about 1.9 g. 
     
     
       24. A chewable or dispersible tablet formulation comprising about 5 to 375 mg of ddI; about 0.5 to 0.6 g calcium carbonate; about 0.2 to 0.3 g magnesium hydroxide; about 0.07 g aspartame; about 0.1 g tablet disintegrant; about 0.3 g sorbitol; about 0.05 g mandarin orange flavor; about 0.03 g magnesium stearate and sufficient microcrystalline cellulose to yield a tablet weighing about 2.1 g.